Bisubstrate Ether‐Linked Uridine‐Peptide Conjugates as O‐GlcNAc Transferase Inhibitors

The O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) transferase (OGT) is a master regulator of installing O‐GlcNAc onto serine or threonine residues on a multitude of target proteins. Numerous nuclear and cytosolic proteins of varying functional classes, including translational factors, transcription factors, signaling proteins, and kinases are OGT substrates. Aberrant O‐GlcNAcylation of proteins is implicated in signaling in metabolic diseases such as diabetes and cancer. Selective and potent OGT inhibitors are valuable tools to study the role of OGT in modulating a wide range of effects on cellular functions. We report linear bisubstrate ether‐linked uridine‐peptide conjugates as OGT inhibitors with micromolar affinity. In vitro evaluation of the compounds revealed the importance of donor substrate, linker and acceptor substrate in the rational design of bisubstrate analogue inhibitors. Molecular dynamics simulations shed light on the binding of this novel class of inhibitors and rationalized the effect of amino acid truncation of acceptor peptide on OGT inhibition. Blocking the master regulator: O‐GlcNAcylation is one of the prominent hallmarks of cancer, and O‐GlcNAc transferse (OGT) is solely responsible for this post‐translational modification. The basic design of bisubstrate inhibitors consists of the donor substrate and acceptor substrate analogues tethered via a suitable linker. In this study a linear bisubstrate analogue inhibitor demonstrated significant inhibitory activity against hOGT in vitro at micromolar concentrations.